Pain is an unpleasant sensation in animals that is caused by actual or perceived injury to body tissues and produces physical and emotional reactions. Presumably, pain sensation has evolved to protect our bodies from harm by causing us to perform certain actions and avoid others. Pain might be called as a protector, a predictor, or simply a hassle (William C. Shiel, ‘Pain Management’ Medicine Net, June 2018).
We all experience pain to greater or lesser extent at various points of our lives. Plausibly pain is the most common reason that patients seek medical attention. But, each of us perceives a given pain stimulus in our own unique manner. The intensity of the response to a pain stimulus is largely subjective.
Pain is actually a wide spectrum of disorders including acute pain, chronic pain and cancer pain and sometimes a combination of these. Pain can also arise for many different reasons such as surgery, injury, nerve damage, physical changes; changes in mood; decrease in appetite; and metabolic problems such as diabetes.
‘Nerve pain’ is often caused due to nerve damage. Nerve damage from diabetes is called diabetic neuropathy. About half of all people with diabetes have some form of nerve damage. It is more common in those who have had the disease for a number of years and can lead to many kinds of health problems.
The damaged nerve performs functions abnormally. It may become quiet and send no information, which causes numbness, or it may send excessive and inappropriate pain messages.
Typically pain is classified as either acute or chronic. Acute pain is of abrupt onset and is usually the result of a clearly defined cause such as an injury. Acute pain resolves with the healing of its underlying cause.
On the other side chronic pain persists for weeks or months and is usually associated with an underlying condition, such as arthritis. The severity of chronic pain can be mild, moderate, or severe. The chronic pain is associated with lower back pain, arthritis, headache, multiple sclerosis, fibromyalgia, shingles, nerve damage, or cancer. In some instances the pain is neuropathic pain, inflammatory pain, nociceptive pain, functional pain, musculo-skeletal pain, peripheral and central nervous system pain.
‘Neuropathic pain’ is pain caused by damage or disease that affects the nervous system.
Classic examples of this pain are shingles and diabetic peripheral neuropathy. Diabetic peripheral neuropathy (DPN) damages two different types of nerves close to the surface of human skin. DPN can affect small nerves that protect human body by sending signals about pain and temperature changes to brain. This condition can also attack large nerves that detect touch, pressure and help to keep a balance. Most people with DPN have damage to both types of nerves [American Diabetes Association. Diabetes Care 2017; 40:136-154.]
DPN usually affects extremities like feet, hands, legs and arms, where nerve fibers are the longest and most numerous. The International Association for the Study of Pain (IASP) defines ‘neuropathic pain’ as pain caused by a lesion or disease of the somatosensory nervous system, which causes unpleasant and abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia).
According to recent studies, it is observed that neuropathic pain affects about 1 in every 10 adults and the economic burden for treating this pain is increasing. Langley et al [J Med Econ. 2013; 16(1):85-95] have described economical and social impact of neuropathic pain (NeP) on health-related quality-of-life in Western Europe.
Neuropathic pain [NeP] severity is associated with loss of productivity and needs more visits to the physician and higher number of medications for treatment. The economic burden of NeP is a significant concern in developing countries like India. Neuropathic pain [NeP] is a severe and debilitating condition which affects approximately 4 million people in the India alone. Though reports are limited on the prevalence of NeP, the burden of NeP in India is enormous. In a recent evaluation from India, the reported prevalence of diabetic peripheral neuropathy (DPN) was 29.2% in patients with type 2 diabetes mellitus (T2DM). A recent consensus document from India provides recommendations for pharmacological treatment of pain. However, despite the knowledge of damaging complications of neuropathies, there are no specific guidelines or consensus recommendations on the diagnosis and treatment of NeP in Indian setting [Indian Journal of Pain, 32,3, 2018].
Particularly, neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
There are further types of neuropathy such as autonomic neuropathy which affects the autonomic nerves, which control the bladder, intestinal tract, and genitals, among other organs; neuropathic arthropathy; cranial neuropathy, compression mononeuropathy, femoral neuropathy, diabetic amyotrophy, focal neuropathy, thoracic or lumbar radiculopath.
The treatment of pain is guided by the history of the pain, its intensity, duration, aggravating and relieving conditions, and structures involved in causing the pain. In order for a structure to cause pain, it must have a nerve supply, be susceptible to injury, and stimulation of the structure should cause pain. The concept behind most interventional procedures for treating pain is that there is a specific structure in the body with nerves of sensation i.e. generating the pain.
Pain management has crucial role in identifying the precise source of the problem and isolating the optimal treatment.
There are mainly four types of pharmacological therapies for neuropathic pain that are widely used in the medical sector: antidepressants, anticonvulsants, opioids, and topical agents.
The first-line treatments for neuropathic pain, based on efficacy and safety, include antidepressants (e.g., tricyclic antidepressants [TCAs], serotonin-norepinephrine reuptake inhibitors [SNRIs]) and certain anticonvulsants (e.g., gabapentin, pregabalin, and topical lidocaine). Opioid analgesics have been recommended as second-line treatments, given their safety; however, they are sometimes used as first choice. Third-line treatments include certain antidepressant medications (e.g., bupropion, citalopram, and paroxetine) and certain anticonvulsants medications (e.g., carbamazepine, lamotrigine, oxcarbazepine, and N-methyl-D-aspartate [NMDA] receptor antagonists). However, these drugs are not completely effective in attenuating neuropathic pain, because of the complexity of this type of pain, and also accompanied with side effects, such as sedation, dizziness, edema, and ataxia. For these reasons, there is interest developed in finding alternate non toxic, environmentally friendly agents for relieving neuropathic pain.
Diet and nutrition are frequently overlooked as a first-line tool for pain relief. It is observed that certain nutrients can influence pain without causing side effects; such nutrients also may present as therapeutic candidates for the development of new drugs to alleviate neuropathic pain.
Further the neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, plays an important role in the induction and maintenance of chronic pain and neuropathic pain.
In the past few years fatty acid amides are found to be effective to relieve the chronic inflammatory and neuropathic pain. Fatty acid amides include anandamide (N-arachidonoylethanolamine), oleamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA).
Among fatty acid amides PEA, an endogenous fatty acid amide belonging to the N-acylethanolamines family, exhibit efficacious results in patients with chronic pain associated to a variety of pathological conditions.
‘PEA’ is effective and safe in the management of chronic pain in different pathological conditions, without any adverse effects.
Schifilliti C, et al. discloses therapeutic use of micronized palmitoylethanolamide for reducing symptoms of neuropathic pain in diabetic patients. (Pain Res Treat 2014; 2014: 849623).
US20170252314A1 discloses method for controlling the inflammatory and/or neuropathic pain of various origins by administering a pharmaceutical composition comprising palmitoylethanoiamide (PEA) and L-acetylcarnitine (LAC), optionally in addition with an antioxidant compound, such as a polyphenol, alpha-lipoic acid, or 1-acetylcysteine to a patient.
U.S. Pat. No. 9,801,836B2 discloses pharmaceutical compositions comprising N-palmitoylethanolamide as an analgesic in combination with opioids for treating pain conditions.
It is reported that ‘opioids’ are effective to some extent in reducing the intensity of some neuropathic pain states. However, these drugs commonly cause side effects expressed as cognitive ability, constipation and nausea, and their use is further limited by the risk of abuse of the opioid.
WO2016183134A1 discloses composition comprising palmitoylethanolamide and salicylate for reducing or alleviating pain in a subject in need thereof.
WO2016146453A1 relates to composition comprising palmitoylethanolamide (PEA) and a vitamin B for alleviating neuropathic pain and method for preparing such a composition.
WO2013063263A1 discloses compositions comprising anti-depressant agomelatine or related compounds together with palmitoylethanolamide (PEA) as a co-factor, for the prevention or treatment of neuropathic pain.
Currently, various drugs are used to combat neuropathic pain, though without reaching the desired level of success for the patient. Side effects induced by current prescribed pain-relieving drugs limit their use by making it impossible to reach effective dose levels. So, there is a need for effective and safe treatment options for patients suffering from neuropathic pain.
Accordingly, research continues into new or alternative remedy for treating neuropathic pain in a manner that is long lasting, effective, with few side effects and good tolerability.
The disabling human syndrome of “neuropathic pain” is difficult complication of peripheral or central nerve injury or degeneration. A complex interaction between injured peripheral axons, sensory neurons and central nervous system signaling is intended to account for it.
It is evident that that the free radical signaling molecule, nitric oxide (NO) may act at several levels of the nervous system during the development of experimental neuropathic pain. It may be an important player in the cascade of events that generate neuropathic pain.
‘Nitric Oxide’ (NO) may be involved in the mechanisms of pain generation and transmission throughout the central and peripheral nervous systems (including brain and spinal cord and perivascular tissue and peripheral nerve terminals) and locally released pain mediators (including formation of inflammation and vascular edema). These novel observations prescribe new approaches to the pharmacologic treatment of neuropathic pain, and other forms of chronic, intractable pain that are resistant to classical pharmacotherapy.
U.S. Pat. No. 9,649,334B2 pertains to a method of treating peripheral neuropathy in a human subject, the method comprising: orally administering to the subject a pharmaceutical composition comprising about 40 mg of sodium nitrite one or two times per day for at least ten days.
U.S. Pat. No. 9,561,249B2 discloses a method of treating or reducing neuropathic pain, said method consisting of orally administering to a subject in need thereof a tablet or capsule formulated for sustained release of inorganic nitrite i.e. KNO2 or NaNO2.
U.S. Ser. No. 10/383,903B2 discloses an extract of amaranth, having enriched nitrate content, L-arginine, flavonoids, saponins, alkaloids, carbohydrates, proteins, potassium, for lowering the blood pressure (hypertension) and increasing the endurance.
The new strategies of pharmacologic pain treatment are increasing rapidly due to the availability of new drugs modulating the NO-activated cascade.
To overcome the side effect of opioids and other analgesic substances in pharmacologic pain treatment, the present inventors have successfully formulated synergistic nutritional composition of fatty acid amide in presence of NO modulator.